Parkinson's disease (PD) afflicts roughly 1 in 1000 adults, rising exponentially in incidence after the age of fifty. Human and animal studies have shown that parkinsonism results from the degeneration of the mesencephalic dopaminergic neurons ? In PD patients and in primate PD models, the electrical activity of neurons in globus pallidus (GP) and the subthalamic nucleus (STN) is abnormal. Unlike neurons from normal animals, GP and STN neurons in these animals exhibit synchronous, rhythmic burst discharges. It has been hypothesized that this abnormal activity is responsible for the motor symptoms in PD, providing a rationale for surgical intervention either in the form of pallidal electrolytic lesions or deep brain stimulation of the STN. It is the central hypothesis of this program proposal that the abnormal activity responsible for the symptoms of PD is attributable to adaptations in intrinsic properties of GP and STN neurons and their synaptic interaction following dopamine (DA) depletion. To test this hypothesis, the program brings together four groups with well-established expertise in the electrophysiological analysis of basal ganglia function. The first three projects will use a combination of molecular, pharmacological and electrophysiological approaches to study intrinsic ionic and synaptic mechanisms governing the activity patterns of GP and STN neurons and how these mechanisms are modulated by dopamine. Project 1 (Surmeier) first will generate a molecular and biophysical characterization of voltage-dependent and ligand-gated ion channels governing discharge in identified neurons of the rodent GP and then show how these channels are modulated by dopamine. A combination of !single cell RT-PCR, voltage-clamp and current clamp approaches will be used in acutely-isolated neurons and neurons in tissue slices. Project 2 (Bevan) will provide a similar level of analysis of identified rodent STN neurons using a common set of experimental approaches, in addition to anatomical strategies? Project 3 (Kita) will focus on how STN glutamatergic synaptic input regulates GP neuron activity and how alterations in this input might lead to dyskinesias. These studies will utilize pharmacological, anatomical and electrophysiological approaches in rodents and behaving primates. Project 4 (Wilson) brings these experimental results together to forge biologically grounded compuational model of the GP/STN circuit in normal and dopamine-depeleted states? The successful attainment of these program aims should provide critical information about DA-depletion induced adaptations in basal ganglia neurons most directly linked to the motor symptoms ofPD - placing the neuroscience community in a much better position to devise new and more effective pharmacological and genetic treatments for this debilitating disease.